1. Field of the Invention
This invention relates to a method of preventing or inhibiting reperfusion injury to the ischemic myocardium, comprising administration of adenosine or an adenosine receptor agonist via a catheter prior to reperfusion of the myocardium.
2. Introduction
Coronary arteries are subject to atherosclerosis. During this process, plaque forms within vascular regions, resulting in stenosed regions having reduced cross-sectional area. The reduced area causes a reduction in transport of blood, oxygen, and nutrients through the arteries, which can result in ischemia, necrosis, angina, myocardial infarction, and ultimately death.
A commonly used method for treating atherosclerosis is percutaneous transluminal coronary angioplasty (PTCA). PTCA includes insertion of a balloon catheter into the blocked coronary artery, and continuing until the uninflated balloon portion is placed across the stenosed region. The balloon is inflated, physically widening the narrowed vessel. The balloon is then deflated, thus causing reperfusion of the artery.
Unfortunately, reperfusion, although it relieves or reduces the problems caused by ischemia, is often followed by morphological and functional changes that ultimately result in tissue damage known as reperfusion injury, which significantly reduces the benefit of reperfusion. Reperfusion injury can be caused by either an acceleration of processes initiated during ischemia per se, or new pathophysiological changes that are initiated by the reperfusion itself. As a result, myocardium that was viable at the end of the ischemic period may nonetheless lose viability during reperfusion.
Although the precise mechanism of reperfusion injury is uncertain, there is support for neutrophil-mediated cell injury as a contributing factor. Other possible mechanisms include platelet aggregation, vascular injury, local release of vasoactive substances, and depletion of the myocardial nucleotide pool.
Adenosine, an endogenous purine nucleoside, antagonizes many of the biochemical and physiological mechanisms implicated in reperfusion injury. However, adenosine is unsuitable for conventional administration, for example orally. Adenosine has a short half life in blood plasma, and is thus also unsuitable for IV administration.
It is known that adenosine attenuates ischemia-reperfusion injury of the heart upon administration prior to ischemia. Ely, S W et al., J. Thorac Cardiovasc Surg 90:549-556, 1985; Olafsson B, et al. Circ 76:1135-1145, 1987; Lasley, R D, et al., Am J Physiol 263:H1460-H1465, 1992; Ely S W, Berne R M, Circ 85:893-904, 1992; Janier, M F, et al., Am J Physiol 264:H163-H170, 1993; Zhao, Z Q, et al. Circ 88:709-719, 1993. It has been postulated that adenosine provides a protective effect by acting on A1 adenosine receptors or on A2 adenosine receptors.
Thus, it would be useful to provide a method for delivering adenosine, or compounds that are A1 and/or A2 adenosine receptor agonists, to a reperfused site in a manner that prevents reperfusion injury, in particular to a reperfused site following angioplasty.
In one aspect, the invention provides a method of preventing or inhibiting ischemia-reperfusion injury to a human following angioplasty, comprising:
a) positioning a balloon catheter proximate to the obstruction of the infarct-related artery and inflating the balloon;
b) contacting the distal vascular bed with an adenosine receptor agonist; and
c) deflating the balloon.
Optionally, the dilated coronary segment can be stented following treatment.
The adenosine receptor agonist is preferably chosen from adenosine, or an A1 and/or A2 adenosine receptor agonist. Preferred A1 or A2 adenosine receptor agonists are adenosine, N-[(3R)-tetrahydro-3-furanyl] (CVT 510) and 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxalan-2-yl)]-6-aminopurine-2-yl}pyrazol-4-yl)-N-methylcarboxamide (CVT-3146). Most preferably, the compound chosen for administration is adenosine, which is introduced into the distal bed via injection.